Prediction of membrane protein structures with complex topologies using limited constraints
Prediction of membrane protein structures with complex topologies using limited constraints
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DOI：
10.1073/pnas.0808323106
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发表时间：
2009-02-03
影响因子：
11.1
通讯作者：
Baker, D.
中科院分区：
文献类型：
--
作者：
Barth, P.;Wallner, B.;Baker, D.
可靠的膜蛋白结构预测方法非常重要，因为高分辨率膜蛋白结构的实验测定仍然非常困难，特别是对于真核蛋白。然而，膜蛋白的长度通常超过 200 个氨基酸，这对于结构预测来说是一个巨大的挑战。我们开发了一种通过将螺旋-螺旋堆积排列限制在从序列预测或通过实验鉴定的特定位置来预测大膜蛋白结构的方法。我们在 12 种具有不同拓扑和功能、长度在 190 到 300 个残基之间的膜蛋白上测试了该方法。在折叠模拟过程中实施单一约束丰富了 9 种蛋白质的近天然模型群体。在根据序列预测约束的 4 个案例中，5 个最低能量模型中的 1 个可在原生结构上 4 埃内叠加。还可以从模拟中选择近天然结构作为血红素结合和成孔结构域，其中一对保守的组氨酸螯合血红素和一个实验确定的盐桥分别受到限制。这些结果表明，如果可以从蛋白质结构数据库或实验中获得有关残基-残基相互作用的有限信息，则可以为复杂膜蛋白实现 4 埃以内的模型。
Reliable structure-prediction methods for membrane proteins are important because the experimental determination of high-resolution membrane protein structures remains very difficult, especially for eukaryotic proteins. However, membrane proteins are typically longer than 200 aa and represent a formidable challenge for structure prediction. We have developed a method for predicting the structures of large membrane proteins by constraining helix-helix packing arrangements at particular positions predicted from sequence or identified by experiments. We tested the method on 12 membrane proteins of diverse topologies and functions with lengths ranging between 190 and 300 residues. Enforcing a single constraint during the folding simulations enriched the population of near-native models for 9 proteins. In 4 of the cases in which the constraint was predicted from the sequence, 1 of the 5 lowest energy models was superimposable within 4 angstrom on the native structure. Near-native structures could also be selected for heme-binding and pore-forming domains from simulations in which pairs of conserved histidine-chelating hemes and one experimentally determined salt bridge were constrained, respectively. These results suggest that models within 4 angstrom of the native structure can be achieved for complex membrane proteins if even limited information on residue-residue interactions can be obtained from protein structure databases or experiments.